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Int J Mol Sci. 2016 Nov 1;17(11). pii: E1824.

Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency.

Author information

1
Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland. jayasimman.rajendran@helsinki.fi.
2
Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland. jayasimman.rajendran@helsinki.fi.
3
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. nikica.tomasic@med.lu.se.
4
Department of Neonatology, Karolinska University Hospital, 17176 Solna, Sweden. nikica.tomasic@med.lu.se.
5
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. heike.kotarsky@gmail.com.
6
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. eva.hansson@med.lu.se.
7
Finnish Institute of Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland. vidya.velagapudi@helsinki.fi.
8
Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland. jukka.kallijarvi@helsinki.fi.
9
Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland. vineta.fellman@med.lu.se.
10
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. vineta.fellman@med.lu.se.
11
Institute of Clinical medicine, Children's Hospital, Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland. vineta.fellman@med.lu.se.

Abstract

Mitochondrial disorders cause energy failure and metabolic derangements. Metabolome profiling in patients and animal models may identify affected metabolic pathways and reveal new biomarkers of disease progression. Using liver metabolomics we have shown a starvation-like condition in a knock-in (Bcs1lc.232A>G) mouse model of GRACILE syndrome, a neonatal lethal respiratory chain complex III dysfunction with hepatopathy. Here, we hypothesized that a high-carbohydrate diet (HCD, 60% dextrose) will alleviate the hypoglycemia and promote survival of the sick mice. However, when fed HCD the homozygotes had shorter survival (mean ± SD, 29 ± 2.5 days, n = 21) than those on standard diet (33 ± 3.8 days, n = 30), and no improvement in hypoglycemia or liver glycogen depletion. We investigated the plasma metabolome of the HCD- and control diet-fed mice and found that several amino acids and urea cycle intermediates were increased, and arginine, carnitines, succinate, and purine catabolites decreased in the homozygotes. Despite reduced survival the increase in aromatic amino acids, an indicator of liver mitochondrial dysfunction, was normalized on HCD. Quantitative enrichment analysis revealed that glycine, serine and threonine metabolism, phenylalanine and tyrosine metabolism, and urea cycle were also partly normalized on HCD. This dietary intervention revealed an unexpected adverse effect of high-glucose diet in complex III deficiency, and suggests that plasma metabolomics is a valuable tool in evaluation of therapies in mitochondrial disorders.

KEYWORDS:

BCS1L; GRACILE syndrome; dextrose diet; metabolite; mitochondrial disorder; mouse model; nutrition

PMID:
27809283
PMCID:
PMC5133825
DOI:
10.3390/ijms17111824
[Indexed for MEDLINE]
Free PMC Article

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